HIV, SIV, and related lentiviruses of other species are unusual in that their envelope glycoproteins have very long cytoplasmic domains (CD); however, investigation of the functional contributions of the unusually long CDs has received little attention. The proposed studies will build upon a recent discovery made by the Desrosiers laboratory, that the cytoplasmic domains of gp41 (gp41CD) of both HIV-1 and SIV induce robust activation of the transcription factor NF-?B. Binding studies further revealed that gp41CD of HIV-1, but not SIV, interacts specifically and efficiently with TGF--activated Kinase 1 (TAK1), a key regulator of NF-?B signaling. Replication studies with wild-type HIV-1 and a mutant virus deficient in the ability to activate NF-?B demonstrated that NF-?B activation by gp41CD is important for the virus' ability to replicate in non- or minimally-activated CD4+ T-lymphocytes. These findings demonstrated a novel, evolutionarily conserved role for gp41CD in activating the NF-?B transcription factor. The proposed studies are directed toward investigating in precise detail how the cytoplasmic domains of gp41 (gp41CD) of HIV-1 and SIV lead to activation of NF-?B. Biochemical, genetic, and structural studies will focus on defining the signaling events, cellular interaction partners, and molecular mechanisms of gp41CD-induced NF-?B activation for promoting viral replication (Aim 1). Our studies will further determine the physiologic relevance of gp41CD-induced NF-?B activation for SIV replication and pathogenesis in vivo (Aim 2). Taken together, these studies will not only greatly expand our understanding of the modulation of key signaling pathways by HIV/SIV gp41, but may also define new therapeutic targets for the treatment of HIV infection in humans.